The LSD high affinity binding sites shared with 5-hydroxytryptamine will be characterized by thermodynamic and kinetic studies, and the interaction of these sites with related compounds will be appraised. Analogous methods will be used to characterize the high affinity sites for mescaline. The thermodynamic results will be compared with reactivity characteristics of molecules obtained by quantum chemical calculations. The kinetic results will test hypotheses, from quantum chemical calculations, on drug-receptor interactions and the electronic basis of receptor activation. For quantum mechanical calculations, we will use ab-initio all electron and pseudopotential LCAO-SCF methods. The contribution of electron correlation energies to the stabilization of simulated drug-receptor complexes will also be calculated. Electrostatic approximations and perturbation methods will be used to obtain potential energy surfaces in simulations of drug receptor complexes. We will calculate the molecular determinants for the affinities of drugs for the receptors, searching for discriminant characteristics that determine interactions with different receptors. Additional compounds will be tested to probe hypotheses. Binding characteristics will be studied in the presence of ions and guanyl nucleotides and after treating the membranes with site-targeted chemicals. The LSD/5-HT receptor defined by binding studies will be compared with the 5-HT receptor linked to adenylate cyclase, which is competitively blocked by LSD. Neuroanatomic techniques will be used to delineate the localization of the binding sites for LSD and mescaline by radioautography in vitro on brain slices, both to learn the neural systems with which these hallucinogens interact and to guide our binding studies on homogenates.